ABSTRACT Stroke is the leading cause of disability in the United States, with approximately 700,000 new cases per year. Disability from upper limb impairment depends primarily on loss of hand function and finger dexterity. Despite advances in task-specific training for the upper limb, a large number of stroke patients do not regain full function of their hand. Somatosensory peripheral nerve stimulation (PNS) is a promising approach to target recovery of hand motor function in stroke patients. Both short-term and long-term improvements in hand function after stimulation of the peripheral nerves have been demonstrated in stroke patients. However, not all studies have found consistent effects and not all participants have experienced significant benefits. Improvements have also been linked to changes in central nervous system motor networks. Very little is known, however, about how PNS interacts with cortical neurophysiological dynamics. A systematic determination of dosing requirements and mechanisms of action is required for robust clinical translation and for maximal functional restoration in those with chronic motor deficits. Our proposal aims to take an innovative and comprehensive approach involving both human subjects and an animal model of stroke to better target perilesional cortical dynamics. Importantly, our preliminary data in both animals and human stroke subjects demonstrates a link between PNS and changes in resting state cortical dynamics. Our proposal is based on the overall hypothesis that dose titration to specifically target perilesional cortical activity will offer a more robust path to reliable translation and customization of parameters to individuals. Using a within subject study design and kinematic and neurophysiological outcome measures, we propose to conduct studies that will delineate how to modify and structure peripheral nerve stimulation to maximize functional restoration. Completion of our aims will provide essential guidance for the refinement and robust translation of peripheral neuromodulation to stroke patients. Our studies will allow us to: (1) definitively and causally determine how perilesional cortical activity is modified by PNS and (2) determine the link between perilesional cortical activity modulation and motor behavioral effects. We anticipate that we can develop a computational model of how cortical activity is modified in a gradual manner by ongoing PNS. This may allow us to develop novel approaches to PNS that are tailored to ongoing cortical dynamics and highly individualized for each stroke patient's specific pattern of injury.